US3847822A - Asymmetric membrane of polyvinyl pyrrolidone-cellulose acetate blends for use as hemodialysis membranes - Google Patents
Asymmetric membrane of polyvinyl pyrrolidone-cellulose acetate blends for use as hemodialysis membranes Download PDFInfo
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- US3847822A US3847822A US00256512A US25651272A US3847822A US 3847822 A US3847822 A US 3847822A US 00256512 A US00256512 A US 00256512A US 25651272 A US25651272 A US 25651272A US 3847822 A US3847822 A US 3847822A
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- cellulose acetate
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- hemodialysis
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- 239000012528 membrane Substances 0.000 title claims abstract description 71
- 229920002301 cellulose acetate Polymers 0.000 title claims abstract description 27
- 238000001631 haemodialysis Methods 0.000 title claims abstract description 14
- 230000000322 hemodialysis Effects 0.000 title claims abstract description 14
- 239000000203 mixture Substances 0.000 title description 15
- 229920002554 vinyl polymer Polymers 0.000 title description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 15
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 15
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 13
- 102000009027 Albumins Human genes 0.000 claims abstract description 10
- 108010088751 Albumins Proteins 0.000 claims abstract description 10
- 229920001202 Inulin Polymers 0.000 claims abstract description 8
- 229940029339 inulin Drugs 0.000 claims abstract description 8
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 claims abstract description 8
- 239000008240 homogeneous mixture Substances 0.000 claims abstract description 3
- 238000000108 ultra-filtration Methods 0.000 description 18
- 230000032258 transport Effects 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000000502 dialysis Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005266 casting Methods 0.000 description 7
- 239000012527 feed solution Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 230000035699 permeability Effects 0.000 description 6
- 150000001242 acetic acid derivatives Chemical class 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000001453 nonthrombogenic effect Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000012466 permeate Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 206010053567 Coagulopathies Diseases 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 208000037157 Azotemia Diseases 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001879 gelation Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001223 reverse osmosis Methods 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- VVHOUVWJCQOYGG-REOHCLBHSA-N N-amidino-L-aspartic acid Chemical compound NC(=N)N[C@H](C(O)=O)CC(O)=O VVHOUVWJCQOYGG-REOHCLBHSA-N 0.000 description 1
- 241000736022 Sansevieria cylindrica Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000005442 diisocyanate group Chemical group 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical class [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000005357 flat glass Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007655 standard test method Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/08—Polysaccharides
- B01D71/12—Cellulose derivatives
- B01D71/14—Esters of organic acids
- B01D71/16—Cellulose acetate
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/44—Polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds, not provided for in a single one of groups B01D71/26-B01D71/42
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/44—Polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds, not provided for in a single one of groups B01D71/26-B01D71/42
- B01D71/441—Polyvinylpyrrolidone
Definitions
- This invention relates to hemodialysis membranes and more particularly this invention relates to a polyvinyl pyrrolidone-cellulose acetate blend.
- Cellulose acetate membranes of the asymmetric or active layer type have been prepared for this purpose. These membranes are characterized by a very thin, dense active layer surmounting a relatively thick layer having an open-cell sponge-like structure with borders of about 0.5 micron diameter. Such a membrane has been used for desalination by reverse osmosis. In dialysis, however, unlike reverse osmosis, it was recognized that the porous substructure could impede the transport of solutes by concentration polarization in the dialysate solution filling its pores. If, on the other hand, the pores allowed circulation of fluid, increased transport rates could be realized due to the extreme thinness of the active layer.
- a membrane is cast containing a blend of cellulose acetate and polyvinyl pyrrolidone.
- Polyvinyl pyrrolidone is a stable water-soluble polymer that physiologically resembles plasma protein. It was originally used as a blood expander during World War II and since then a variety of pharmaceutical and cosmetic applications have been developed. Recently, one investigator obtained a Lee-White clotting time of 105 minutes on a heparinized polyvinyl pyrrolidone (5%) acrylamide (18%) hydrogel, and an unheparinized clotting time of 47 minutes.
- a number of membrane characteristics are important to their application in hemodialysis and, therefore, are evaluated either directly or indirectly.
- the mass transport of solutes by dialysis and of water by ultrafiltration are, of course, important.
- the membranes must also exhibit satisfactory tensile strength and sufficient elongation to conform to seals without rupture.
- ultrafiltration cells were used for the preliminary evalution of all membranes.
- the feed solution under pressure, is circulated across the active layer of the membrane and a portion of the water and of the solutes permeate the membrane.
- the ratio of the concentration of a solute in the permeate to its concentration in the feed gives a measure of the porosity of the membrane, and the rate of permeate flow is the ultrafiltration rate.
- the ultrafiltration cells used on the current program expose 29.4 sq. cm. of a circular membrane having a diameter of three inches to the feed solution at a pressure of one atmosphere.
- the ultrafiltration test has proven to be a rapid method of comparing the ultrafiltration rates of membranes for hemodialysis. It has also been useful for the detection of membranes of excessive porosity, i.e., membranes which transport albumin.
- the ultrafiltration rates are reported as ml./min.-m. -min. Hg (X10 A solute permeation (SP) expressed as a percentage is used to denote the ratio of the concentration of a solute in the permeate to its concentration in the feed solution.
- the studies are conducted with a solution containing about 8,500 p.p.m. of sodium chloride, and p.p.m. of inulin in a 0.01 M phosphate buffer (310 p.p.m. phosphorous).
- the phosphate buffer prepared from a mixture of monoand disodium phosphates, is included to maintain the feed solution without a pH range of 7.2 to 7.4.
- the standard test solution for the ultra-filtration cell is prepared by the addition of 1000 p.p.m. of albumin to the above solution.
- the dialysis and transport of other solutes, especially those metabolites characteristic of the uremic syndrome, should be considered. Guanidinosuccinic acid is of special interest in this respect.
- the permeation characteristics of asymmetric membranes may often be correlated with their physical properties because both depend on membrane structure. Also, a compromise must be reached between the permeation characteristics and the mechanical properties in the preparation of the optimum dialysis membrane.
- the membranes are cast using procedures which are well-known in the art.
- the blend of cellulose acetate and polyvinyl pyrrolidone is dissolved in any solvent system which is compatible for dissolving both polymers.
- solvent system is meant any single solvent or combination of solvents which meet the requirements of compatibility.
- Exemplary of such a solvent is 1-methyl-2-pyrrolidone and a typical representative solvent system containing more than one ingredient is a mixture of acetone and glacial acetic acid.
- the solution could also include a small proportion of water in order to impart certain characteristics to the drying of the solution, as long as the proportion of water used does not cause gelling or blushing. Other characteristics of solvents may be utilized such as the difference in volatility or hydrophobicity.
- a more volatile solvent is used, the rate of solvent loss during the limited drying time can be utilized to achieve the same effect as an extended drying time.
- a more hydrophobic solvent, compatible with the polymers could be used which does not retard the loss of organic solvent but does retard the diffusion of water into the membrane during gelation. This should also effectively increase the polymer concentration in the liquid casting solution formulation just prior to and during gelation. Additionally, other characteristics which can be easily determined by one of ordinary skill in the art can be adjusted by casting membranes from polymers of different molecular weights.
- polymers falling within a wide range of molecular weights can be used, the only limitation being that they be of a molecular weight which can be cast into a film by the ordinary procedures, and exhibit the desirable dialysis and ultrafiltration characteristics such as retaining albumin which has a molecular weight of approximately 60,000 while showing high transport rate for solutes of low molecular weight.
- the casting solution is made by dissolving the blend of polyvinyl pyrrolidone and cellulose acetate in sufficient solvent system to reduce the viscosity of the casting solution so that it can be easily handled. Generally, this will fall into a range of about 200 to about 500 parts of solvent per 100 parts of polymer blend.
- the membranes are prepared by casting a film of the solution on glass at ambient temperature. The film is cast to a thickness of about 8 mils and gelled in ice water. A short drying time, up to about 60 seconds, could be used, but in the preferred method the film is immediately gelled without any drying time.
- the film cast on the glass is allowed to set in the ice water for a time sufiicient to allow the same to soak loose from the glass plate. This time could range from about 10 to minutes.
- the membrane is then tested using the aforementioned procedures.
- An asymmetric membrane was prepared from a polyvinyl pyrrolidone-cellulose acetate blend according to the foregoing procedure using a casting solution formulation containing polyvinyl pyrrolidone 360 (Mann Research Laboratory), cellulose acetate E-400- (Eastman Kodak), acetone and glacial acetic acid in 2,8,40 and 5 parts by weight, respectively. Films of 8 mils thickness were cast on a flat glass plate at room temperature (25 C.) and immediately gelled in ice water. A 2.76 mil thick membrane prepared as described was evaluated under conditions of ultrafiltration at 25 C. and 14.7 p.s.i.g. using a feed solution consisting of 150 p.p.m.
- inulin molecular weight of about 5,000
- 1,000 p.p.m. human albumin molecular weight of about 67,000
- the buffered saline solution contained 8500 p.p.m. sodium chloride in 0.01 M phosphate buffer of pH 7.2.
- the hydraulic permeability and permeation were determined and compared with typical values for Cuprophan.
- the membranes according to the present invention exhibited an inulin permeation value of from about 5.5 to 7.5 times higher and an ultrafiltration rate of about 4 to 7.5 times that of Cuprophan while being equally effective in reflecting albumin.
- An asymmetric hemodialysis membrane comprising a homogeneous mixture of polyvinyl pyrrolidone and cellulose acetate, said membrane being permeable to inulin and essentially impermeable to albumin.
- a membrane as defined in claim 1 having a thickness of from about 1.4 to about 3.0 mils.
- a membrane as defined in claim 3 having a thickness of between about 2 and about 3 mils.
Abstract
1. AN ASYMMETRIC HEMODIALYSIS MEMBRANE COMPRISING A HOMOGENOUS MIXTURE OF POLYVINYL PYRROLIDONE AND CELLULOSE ACETATE, SAID MEMBRANE BEING PERMEABLE TO INULIN AND ESSENTIALLY IMPERMEABLE TO ALBUMIN.
Description
US. Cl. 210-500 4 Claims ABSTRACT OF THE DISCLOSURE Hemodialysis membranes formed of polyvinyl pyrrolidone-cellulose acetate blends are disclosed. The membranes were found to have high inulin permeation values while almost completely reflecting albumin.
BACK-GROUND OF THE INVENTION This invention relates to hemodialysis membranes and more particularly this invention relates to a polyvinyl pyrrolidone-cellulose acetate blend.
Although regenerated cellulose membranes are widely used in hemodialysis, many workers in the field of dialysis assert that improved membranes are needed. There is general agreement that increased transport of blood solutes would be advantageous, but more particularly, many practitioners believe that increased transport of solutes with molecular weights less than albumin but greater than that of uric acid or creatinine could result in improved control of the uremic syndrome. In addition, such dialysis membranes should be nonthrombogenic.
Cellulose acetate membranes of the asymmetric or active layer type have been prepared for this purpose. These membranes are characterized by a very thin, dense active layer surmounting a relatively thick layer having an open-cell sponge-like structure with borders of about 0.5 micron diameter. Such a membrane has been used for desalination by reverse osmosis. In dialysis, however, unlike reverse osmosis, it was recognized that the porous substructure could impede the transport of solutes by concentration polarization in the dialysate solution filling its pores. If, on the other hand, the pores allowed circulation of fluid, increased transport rates could be realized due to the extreme thinness of the active layer. Several methods for controlling the permeability or porosity of the active layer of cellulose acetate membranes were discovered during the course of studies of the structure and transport properties of the same. These methods involve variations in the composition of the casting solution and various modifications of the membrane fabrication procedure. Additionally, studies have been conducted towards the preparation of membranes which are nonthrombogenic or can be made nonthrombogenic by the surface binding of heparin.
Accordingly, it is a primary object of the present invention to provide a hemodialysis membrane having improved permeability and thrombogenic properties.
It is another object of the present invention to provide a hemodialysis membrane which can be easily and cheaply fabricated.
It is still another object of the present invention to provide a hemodialysis membrane which comprises a blend of cellulose acetate and polyvinyl pyrrolidone.
Before describing the instant invention in detail, however, a brief discussion of the various testing methods and standards used is in order. The most commonly used membrane for hemodialysis is made of Cuprophan, which is a reconstituted cellulose made by the cuprammonium process. This membrane is used herein as the standard for comparison.
nited States Patent ice It is noteworthy that membranes prepared from cellulose acetate and other cellulose acetate derivatives have had mass transfer coefiicients equivalent to or higher than Cuprophan in spite of the fact that they were three to five times as thick. Mass transfer coefficients, h are measured with a parallel-plate dialysis cell of the Babb- Grimsrud design. (Lars Grimsrud, A Theoretical and Experimental Investigation of the Performance of a Parallel-Plate Dialyzer in the Laminar Flow Regime, with Applications to Hemodialyzer Design, PhD thesis, University of Washington, 1965; A. L. Babb, C. J. Maurer, D. L. Fry, R. P. Popovich, and R. E. McKee, The Determination of Membrane Permeabilities and Solute Diffusivities with Applications to Hemodialysis, Chem. Eng. Progr. Symposium Serial No. 84, 64, 59 (1968).)
The method used by Grimsrud for the calculation of the mass transfer coefficient, h makes use of the mathematical expression Q A Eq. 1 where Q is the volume rate of flow of feed solution, A is the area of membrane, 0 is the concentration of solute in the feed into the cell, and c is the concentration of solute in the feed coming out of the cell. This expression although apparently satisfactory for the evaluation of Cuprophan, is not applicable to the more open membranes prepared according to the present invention. The difiiculty is that the formula does not take into account changes in feedwater volume which occur on passage through the Babh-Grimsrud cell when it contains a membrane with a very high water transport rate. In initial data, the volume of feed remained unchanged with Cuprophan, decreased with the cellulose acetate membrane, and increased with a cellulose acetate derivative membrane. Therefore, different values for h are obtained from Eq. 1 depending on whether Q, or Q is used, where Q, and Q refer to the volume rate of flow of feed solution into and out of the cell, respectively, and AQ is the rate of volume lost by ultrafiltration or gained by osmosis.
In order to provide for changes in feed volume, Eq. 1 was replaced by the following expression based on heattransfer theory h In Using this modified treatment of the data, it was still observed that membranes with very high water-transport properties exhibit what appear to be anomalous variations in mass transfer coefiicient (h,,) with changes in dialysate flow rates in the Babb-Grimsrud test cell. This phenomenon is exemplified in the following table for the transport of sodium chloride at 25 C. through cellulose acetate and cellulose acetate derivative membranes.
TABLE 1 Dialysate ho (NaCl),
Membrane m1./rnin. (X10 Cellulose acetate 500 455 229 Cellulose acetate derivative 500 269 100 244 3 Standard Test Methods for H emadialysis Membranes, National Bureau of Standards Report No. 9872, July 30, 1968). The relationship specified for the calculation of solute permeability from data obtained from tests using the NBS cell is as follows:
b a b a 1 P: 711 Eq. 3
where,
It must be noted for the NBS cell as well as for the Babb-Grimsrud cell that when evaluating the more permeable membranes it is difficult to fully interpret the experimental data. These difficulties arise due to the high trans port of water by osmotic flow, and of water and solutes by ultrafiltration.
It is believed that the changes in mass transport and permeability values in going from high to low dialysate flow rates in the Babb-Grimsrud dialysis cell can be accounted for by calculated changes in the ultrafiltration rate as a result of the difference in pressure across the membrane in the dialysis cell. Consequently, a change in AP will cause a relatively small change in solute transfer for membranes which exhibit a low ultrafiltration rate. With membranes having high ultrafiltration rates, however, a change in AP will result in a large change in solute transport. This assumption should be easy to confirm by studies using the NBS cell where AP through the membrane may be varied while maintaining constant flow rates on the two membrane surfaces. It appears that in certain cellulose acetate derivative membranes transport of solutes by a diffusive mechanism is more important than in cellulose acetate membranes. In the latter, transport by ultrafiltration or pore flow seems to be the predominant mechanism.
As is well known, certain of the common materials used for dialysis membranes, while having good dialysis properties, tend to be incompatible with blood and to cause clotting. One suggestion to overcome this problem is to chemically modify cellulose acetate with potentially nonthrombogenic groups. The approach taken according to the present invention, however, is to blend cellulose acetate wtih another polymer which either possesses nonthrombogenic properties or can be modified to do so. This modification would take the form of bonding heparin to the polymer.
According to the present invention, a membrane is cast containing a blend of cellulose acetate and polyvinyl pyrrolidone. Polyvinyl pyrrolidone is a stable water-soluble polymer that physiologically resembles plasma protein. It was originally used as a blood expander during World War II and since then a variety of pharmaceutical and cosmetic applications have been developed. Recently, one investigator obtained a Lee-White clotting time of 105 minutes on a heparinized polyvinyl pyrrolidone (5%) acrylamide (18%) hydrogel, and an unheparinized clotting time of 47 minutes. Another investigator prepared a film of polyvinyl pyrrolidone cross-linked with diisocyanate that dialyzed urea more than three times as fast as cellophane. The cross-linking was utilized to insolubilize the water-soluble polyvinyl pyrrolidone. From this previous work, it would be expected that a cellulose acetate-polyvinyl pyrrolidone blend would be slowly soluble. However, it has been recently reported than an ethyl cellulose-polyvinyl pyrrolidone blend from which a film was prepared was complet y insoluble in both gastric and intestinal fluids.
A number of membrane characteristics are important to their application in hemodialysis and, therefore, are evaluated either directly or indirectly. The mass transport of solutes by dialysis and of water by ultrafiltration are, of course, important. For reliability as well as ease of assembly, the membranes must also exhibit satisfactory tensile strength and sufficient elongation to conform to seals without rupture.
Since solutes and water are transported through the membrane by ultrafiltration as well as by diffusion, ultrafiltration cells were used for the preliminary evalution of all membranes. In these cells the feed solution, under pressure, is circulated across the active layer of the membrane and a portion of the water and of the solutes permeate the membrane. The ratio of the concentration of a solute in the permeate to its concentration in the feed gives a measure of the porosity of the membrane, and the rate of permeate flow is the ultrafiltration rate. The ultrafiltration cells used on the current program expose 29.4 sq. cm. of a circular membrane having a diameter of three inches to the feed solution at a pressure of one atmosphere.
The ultrafiltration test has proven to be a rapid method of comparing the ultrafiltration rates of membranes for hemodialysis. It has also been useful for the detection of membranes of excessive porosity, i.e., membranes which transport albumin. The ultrafiltration rates are reported as ml./min.-m. -min. Hg (X10 A solute permeation (SP) expressed as a percentage is used to denote the ratio of the concentration of a solute in the permeate to its concentration in the feed solution.
The studies are conducted with a solution containing about 8,500 p.p.m. of sodium chloride, and p.p.m. of inulin in a 0.01 M phosphate buffer (310 p.p.m. phosphorous). The phosphate buffer, prepared from a mixture of monoand disodium phosphates, is included to maintain the feed solution without a pH range of 7.2 to 7.4. The standard test solution for the ultra-filtration cell is prepared by the addition of 1000 p.p.m. of albumin to the above solution. The dialysis and transport of other solutes, especially those metabolites characteristic of the uremic syndrome, should be considered. Guanidinosuccinic acid is of special interest in this respect.
Modifications of known colorimetric procedures are currently used for all analyses. Sodium chloride concentrations are determined by the use of mercuric chloroanilate as an exchange reactor for ionic chloride (Clinical Methods Manual for Spectronic 20, Bausch and Lomb, 1965 inulin by reaction with anthrone (E. E. Morse, Anthrone in Estimating Low Concentrations of Sucrose, Analytical Chemistry, 19, 1012 (1947)), and albumin by the well-known biuret reaction (Clinical Methods Manual for Spectronic 20, Bausch and Lomb, 1965)), or by the turbidity produced by reaction with trichloroacetic acid (Clinical Methods Manual for Spectronic 20, Bausch and Lomb, 1965), both of which appear in the Bausch and Lomb manual.
The permeation characteristics of asymmetric membranes may often be correlated with their physical properties because both depend on membrane structure. Also, a compromise must be reached between the permeation characteristics and the mechanical properties in the preparation of the optimum dialysis membrane.
The membranes are cast using procedures which are well-known in the art. The blend of cellulose acetate and polyvinyl pyrrolidone is dissolved in any solvent system which is compatible for dissolving both polymers. By solvent system is meant any single solvent or combination of solvents which meet the requirements of compatibility. Exemplary of such a solvent is 1-methyl-2-pyrrolidone and a typical representative solvent system containing more than one ingredient is a mixture of acetone and glacial acetic acid. The solution could also include a small proportion of water in order to impart certain characteristics to the drying of the solution, as long as the proportion of water used does not cause gelling or blushing. Other characteristics of solvents may be utilized such as the difference in volatility or hydrophobicity. If a more volatile solvent is used, the rate of solvent loss during the limited drying time can be utilized to achieve the same effect as an extended drying time. On the other hand, a more hydrophobic solvent, compatible with the polymers, could be used which does not retard the loss of organic solvent but does retard the diffusion of water into the membrane during gelation. This should also effectively increase the polymer concentration in the liquid casting solution formulation just prior to and during gelation. Additionally, other characteristics which can be easily determined by one of ordinary skill in the art can be adjusted by casting membranes from polymers of different molecular weights. In general, polymers falling within a wide range of molecular weights can be used, the only limitation being that they be of a molecular weight which can be cast into a film by the ordinary procedures, and exhibit the desirable dialysis and ultrafiltration characteristics such as retaining albumin which has a molecular weight of approximately 60,000 while showing high transport rate for solutes of low molecular weight.
The casting solution is made by dissolving the blend of polyvinyl pyrrolidone and cellulose acetate in sufficient solvent system to reduce the viscosity of the casting solution so that it can be easily handled. Generally, this will fall into a range of about 200 to about 500 parts of solvent per 100 parts of polymer blend. The membranes are prepared by casting a film of the solution on glass at ambient temperature. The film is cast to a thickness of about 8 mils and gelled in ice water. A short drying time, up to about 60 seconds, could be used, but in the preferred method the film is immediately gelled without any drying time.
The film cast on the glass is allowed to set in the ice water for a time sufiicient to allow the same to soak loose from the glass plate. This time could range from about 10 to minutes. The membrane is then tested using the aforementioned procedures.
An asymmetric membrane was prepared from a polyvinyl pyrrolidone-cellulose acetate blend according to the foregoing procedure using a casting solution formulation containing polyvinyl pyrrolidone 360 (Mann Research Laboratory), cellulose acetate E-400- (Eastman Kodak), acetone and glacial acetic acid in 2,8,40 and 5 parts by weight, respectively. Films of 8 mils thickness were cast on a flat glass plate at room temperature (25 C.) and immediately gelled in ice water. A 2.76 mil thick membrane prepared as described was evaluated under conditions of ultrafiltration at 25 C. and 14.7 p.s.i.g. using a feed solution consisting of 150 p.p.m. inulin (molecular weight of about 5,000) and 1,000 p.p.m. human albumin (molecular weight of about 67,000) in buffered saline solution. The buffered saline solution contained 8500 p.p.m. sodium chloride in 0.01 M phosphate buffer of pH 7.2. The hydraulic permeability and permeation were determined and compared with typical values for Cuprophan.
As can be seen, compared to Cuprophan, the membranes according to the present invention exhibited an inulin permeation value of from about 5.5 to 7.5 times higher and an ultrafiltration rate of about 4 to 7.5 times that of Cuprophan while being equally effective in reflecting albumin.
It should be apparent from the foregoing detailed description that the objects set forth hereinabove have been successfully achieved. Moreover, while there is shown and described a present preferred embodiment of the invention, it is to be distinctly understood that the invention is not limited thereto but may be otherwise variably embodied and practiced within the scope of the following claims.
What is claimed is:
1. An asymmetric hemodialysis membrane comprising a homogeneous mixture of polyvinyl pyrrolidone and cellulose acetate, said membrane being permeable to inulin and essentially impermeable to albumin.
2. A membrane as defined in claim 1, wherein said polyvinyl pyrrolidone and said cellulose acetate are present in a ratio of about 1 to 4.
3. A membrane as defined in claim 1, having a thickness of from about 1.4 to about 3.0 mils.
4. A membrane as defined in claim 3, having a thickness of between about 2 and about 3 mils.
References Cited UNITED STATES PATENTS 2,593,540 4/1952 Cornwell et a1. 2l0-22 3,556,305 1/1971 Shorr 210-490 3,483,282 12/1969 Manjikian 106-176 X FRANK A. SPEAR, JR., Primary Examiner
Claims (1)
1. AN ASYMMETRIC HEMODIALYSIS MEMBRANE COMPRISING A HOMOGENOUS MIXTURE OF POLYVINYL PYRROLIDONE AND CELLULOSE ACETATE, SAID MEMBRANE BEING PERMEABLE TO INULIN AND ESSENTIALLY IMPERMEABLE TO ALBUMIN.
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US00256512A US3847822A (en) | 1972-05-24 | 1972-05-24 | Asymmetric membrane of polyvinyl pyrrolidone-cellulose acetate blends for use as hemodialysis membranes |
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US00256512A US3847822A (en) | 1972-05-24 | 1972-05-24 | Asymmetric membrane of polyvinyl pyrrolidone-cellulose acetate blends for use as hemodialysis membranes |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3988245A (en) * | 1971-09-07 | 1976-10-26 | Aqua-Chem, Inc. | Anisotropic polyvinyl formal resin microporous membrane and its preparation |
EP0066408A2 (en) * | 1981-05-19 | 1982-12-08 | Teijin Limited | Porous membrane |
US4508891A (en) * | 1980-07-16 | 1985-04-02 | Imperial Chemical Industries, Plc | Shaped articles formed from polymers capable of exhibiting anisotropic melts |
US4824639A (en) * | 1984-02-29 | 1989-04-25 | Bayer Aktiengesellschaft | Test device and a method for the detection of a component of a liquid sample |
US4851226A (en) * | 1987-11-16 | 1989-07-25 | Mcneil Consumer Products Company | Chewable medicament tablet containing means for taste masking |
EP0592706A1 (en) * | 1992-10-13 | 1994-04-20 | Deutsche Carbone Ag | Use of cellulose ester blend membranes |
US5523095A (en) * | 1993-12-15 | 1996-06-04 | Eastman Chemical Company | Controlled release matrix system using cellulose acetate/polyvinylpyrrolidone blends |
US5536505A (en) * | 1993-12-15 | 1996-07-16 | Eastman Chemical Company | Controlled release matrix system using cellulose acetate/poly-2-ethyl-2-oxazoline blends |
US5670097A (en) * | 1994-12-08 | 1997-09-23 | Minnesota Mining And Manufacturing Company | Method of making blood gas sensors overcoats using permeable polymeric compositions |
-
1972
- 1972-05-24 US US00256512A patent/US3847822A/en not_active Expired - Lifetime
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3988245A (en) * | 1971-09-07 | 1976-10-26 | Aqua-Chem, Inc. | Anisotropic polyvinyl formal resin microporous membrane and its preparation |
US4508891A (en) * | 1980-07-16 | 1985-04-02 | Imperial Chemical Industries, Plc | Shaped articles formed from polymers capable of exhibiting anisotropic melts |
EP0066408A2 (en) * | 1981-05-19 | 1982-12-08 | Teijin Limited | Porous membrane |
EP0066408A3 (en) * | 1981-05-19 | 1984-10-10 | Teijin Limited | Porous membrane |
US4824639A (en) * | 1984-02-29 | 1989-04-25 | Bayer Aktiengesellschaft | Test device and a method for the detection of a component of a liquid sample |
US4851226A (en) * | 1987-11-16 | 1989-07-25 | Mcneil Consumer Products Company | Chewable medicament tablet containing means for taste masking |
EP0592706A1 (en) * | 1992-10-13 | 1994-04-20 | Deutsche Carbone Ag | Use of cellulose ester blend membranes |
US5611930A (en) * | 1992-10-13 | 1997-03-18 | Deutsche Carbone Ag | Cellulose ester blend membranes, process for making same and their use |
US5523095A (en) * | 1993-12-15 | 1996-06-04 | Eastman Chemical Company | Controlled release matrix system using cellulose acetate/polyvinylpyrrolidone blends |
US5536505A (en) * | 1993-12-15 | 1996-07-16 | Eastman Chemical Company | Controlled release matrix system using cellulose acetate/poly-2-ethyl-2-oxazoline blends |
US5670097A (en) * | 1994-12-08 | 1997-09-23 | Minnesota Mining And Manufacturing Company | Method of making blood gas sensors overcoats using permeable polymeric compositions |
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